The following is a summary of “CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial” published in the March 2023 issue of Haematology by Sallman, et al.

Natural killer (NK) group 2D (NKG2D) receptor-based chimeric antigen receptor (CAR) T-cell product CYAD-01 binds eight ligands that are overexpressed across a broad spectrum of hematological malignancies but are mainly lacking on non-neoplastic cells. The initial clinical investigation of a single low-dose infusion of CYAD-01 in patients with relapsed or refractory acute myeloid leukemia, myelodysplastic syndromes, and multiple myeloma provided evidence for the approach’s viability and spurred additional evaluation of CYAD-01. The purpose of this research was to establish whether or not CYAD-01 could be safely dosed in phase 2 without preconditioning or bridging chemotherapy. Patients with acute myeloid leukemia, myelodysplastic syndromes, or multiple myeloma who had previously received at least one line of therapy but had relapsed or been unresponsive to that treatment were eligible to participate in the multicenter THINK study, which was an open-label, dose-escalation, phase 1 study. 

Five hospitals in the US and one in Belgium provided patients for the study. The dose-escalation phase used a 3 + 3 Fibonacci study design, with a schedule of 3 infusions at 2-week intervals, followed by potential consolidation treatment consisting of 3 additional infusions, to evaluate 3 dose levels: 3×108 (dose level 1), 1×109 (dose level 2), and 3×109 (dose level 3) cells per infusion. The primary endpoint was the incidence of dose-limiting toxicities in the entire treated patient population following CYAD-01 infusion. 25 participants were included in the hematological dose-escalation phase between February 6, 2017, and October 9, 2018. During production, 7 patients experienced a failure due to low output, while 2 more were deemed unfit during screening. The CYAD-01 treatment group had 16 people (3 with multiple myeloma and 3 with acute myeloid leukemia at dose level 1; 3 with acute myeloid leukemia at dose level 2; and 6 with acute myeloid leukemia and one with myelodysplastic syndromes at dose level 3). The average follow-up was 118 days (IQR 46–180). Treatment-related adverse events of grade 3 or 4 occurred in 7 patients (44%). 

Five patients, or 31%, across all doses experienced cytokine release syndrome of grade 3 or 4. There was a single case of cytokine release syndrome as a dose-limiting hazard at the third-highest dose tested. There were no treatment-related fatalities, and the MTD was not reached. An objective response was seen in 3 (12%) of 12 patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes. 2 patients with acute myeloid leukemia who responded to CYAD-01 went on to receive allogeneic hematopoietic stem cell transplantation (HSCT), and both are still in long-term remission (5 and 61 months). Several CYAD-01 infusions can be given without preconditioning, and the treatment is highly tolerated and effective against leukemia, but it does not last long unless the patient is subsequently bridged to allogeneic HSCT. The results of this phase 1 study provide credence to the feasibility of using CAR T-cell therapy to target NKG2D ligands. Further clinical trials utilizing NKG2D-based CAR T-cells are necessary to enhance anti-tumor efficacy, maybe through combinatorial antigen targeting methods.